Sunday, 31 May 2015

Yet again: Nivo plus Ipi better than Ipi alone- CheckMate 069

Clinical response, progression-free survival (PFS), and safety in patients (pts) with advanced melanoma (MEL) receiving nivolumab (NIVO) combined with ipilimumab (IPI) vs IPI monotherapy in CheckMate 069 study. NCT01927419

This is a randomised Phase 2 study of Ipi + Nivo versus Ipi alone- please check the scheme in the abstract below- Ipi + Nivo had already 88%  2 year OS in the Phase 1 study.

An update of this trial was already posted at AACR earlier this year.

This trial was for treatment- naive patients, stratified by BRAF status.

Read the abstract here

Background: Combined blockade of T-cell checkpoints by NIVO and IPI demonstrated a high objective response rate (ORR), promising overall survival (OS), and a manageable safety profile in pts with advanced MEL in a phase I study, based on which an appropriate dose was selected for registrational trials. We report efficacy and safety of the NIVO + IPI combination vs IPI alone in treatment-naïve pts with advanced MEL, including pts with poor prognostic factors, in a phase II study.  Methods: Pts (N = 142) with metastatic or unresectable MEL were randomized 2:1 to receive IPI 3 mg/kg combined with either NIVO 1 mg/kg or placebo Q3W × 4, followed by NIVO 3 mg/kg or placebo Q2W until disease progression or unacceptable toxicity. The primary endpoint was ORR in BRAF wild-type (WT) pts. Secondary and exploratory objectives included PFS in BRAF WT pts, ORR and PFS in BRAF V600 mutation-positive (MT) pts, and safety.  Results: In BRAF WT pts (n = 109), ORR was 60% (43/72) for NIVO + IPI; 11% (4/37) for IPI alone (P < 0.0001); complete responses were reported in 12 (17%) and 0 pts, respectively. Median PFS was 8.9 months for the combination vs 4.7 months for IPI alone (= 0.0012). Higher ORR was observed for NIVO + IPI vs IPI in predefined pt subgroups with poor prognostic factors, such as elevated baseline LDH (53% vs 0%) and M1c stage disease (62% vs 25%). Similar ORR and PFS results were observed in 33 BRAF MT pts. Grade 3–4 drug-related adverse events (AEs) were reported in 51% of pts receiving NIVO + IPI vs 20% for IPI alone. The safety profile of NIVO + IPI was similar across pt subgroups, including age. Select AEs related to the combination regimen were consistent with phase I reports and most resolved with immunosuppressive medication ( > 83% across organ categories) with the exception of endocrinopathies. Updated results from a planned data analysis in March 2015 will be presented. Conclusions: NIVO + IPI significantly improved ORR and PFS compared with IPI alone and had a manageable safety profile. The efficacy and safety of the combination was similar across pt subgroups and provided a favorable risk-benefit ratio in treatment-naïve pts with advanced MEL. Clinical trial information: NCT01927419

To note-

objective response rates- 

59% Combo Ipi/ Nivo
11% Ipi

Median PFS was 8.9 months for the combination vs 4.7 months for IPI alone 

median time to response

2.8 months combo
2.7 months Ipi 

This is kind of interesting as it is often said the PD1 works faster than Ipi...

68% of the patients who discontinued because of side effects got a CR or PR!!!

So it continues to work despite people no longer being on the treatment. Actually a very good comment during a different session was that treatment schemes are often not scientifically motivated (it was the scheme tested in a clinical trial, it worked, so we stick with it- the speaker referred to 4 doses of Ipi), so that there would be a point of re-assessing whether different schemes were equally effective but less toxic.

From a patient perspective
while the result is hopeful- more patients will live thanks to the combination Ipi + Nivo- the design of this clinical trial is disappointing as to the comparator as well as the placebo is certainly not used to control for psychological effects (I have seen no evidence into a psychological effects of any kind affecting ORR in Melanoma in the magnitude of 50% difference).

What about Nivo single agent as comparator, e.g. stratified by PDL-1 expression, and trying to figure out which patients already respond to Nivo alone and don't need the more toxic combination??

Please note- 

As we know, EAP available- check on the BMS website- worth checking whether anything outside the US finally coming along.

No comments:

Post a comment